To cite this article: Narula S, Banwell B. Treatment of multiple sclerosis in children and its challenges. Presse Med. (2015), http:// dx.doi.org/10.1016/j.lpm.2014.10.018 Presse Med. 2015; //: ///

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on line on www.em-consulte.com/revue/lpm www.sciencedirect.com

Quarterly Medical Review

Treatment of multiple sclerosis in children and its challenges Sona Narula, Brenda Banwell

Available online:

Perelman School of Medicine at the University of Pennsylvania, Children's Hospital of Philadelphia, Division of Neurology, Philadelphia, PA 19104, United States

Correspondence: Sona Narula, 3501 Civic Center Boulevard, Colket Translational Research Building, 10th floor, Neurology Division, Philadelphia, PA 19104, United States. [email protected]

Multiple sclerosis: from new concepts to updates on management David-Axel Laplaud, Nantes, France The auto-immune concept of multiple sclerosis Bryan Nicol et al., Nantes, France Environmental factors in multiple sclerosis Vasiliki Pantazou et al., Lausanne, Switzerland Update on clinically isolated syndrome Éric Thouvenot, Nîmes, France Update on treatments in multiple sclerosis Laure Michel et al., Montréal, Canada Treatment of multiple sclerosis in children and its challenges Sona Narula et al., Philadelphia, United States Advanced imaging tools to investigate multiple sclerosis pathology Benedetta Bodini et al., Paris, France Update on rehabilitation in multiple sclerosis Cécile Donzé, Lille, France

Summary Though pediatric-onset multiple sclerosis (MS) is a rare disease, providers must be aware of the diagnosis, and of symptoms that herald demyelination, in order to initiate prompt workup and treatment in the appropriate clinical scenarios. Though children with MS do not have significant physical disability at onset, at least a third of patients have cognitive deficits at the time of diagnosis and demonstrate worsening cognitive functioning over time. Pediatric MS patients tend to have high relapse rates and high lesion volumes early in their disease course and warrant early initiation of disease modifying therapy. This review discusses the different treatment options available for pediatric patients with MS, emerging medications, and some of the challenges associated with treating this patient population.

A

bout 2–10% of patients with multiple sclerosis (MS) will have their first symptom before the age of 18 years [1–5]. The majority of children presenting with acute demyelination of the central nervous system (CNS) manifest with acute visual loss (optic neuritis), limb weakness and bladder impairment (transverse myelitis), brainstem symptoms, or with a syndrome characterized by polyfocal deficits associated with encephalopathy (acute disseminated encephalomyelitis [ADEM]). For some children, however, symptoms of demyelination may be subtle and difficult to articulate (sensory symptoms, visual change). In all situations, providers must be alert to the diagnosis of acute demyelination in the pediatric population as prompt diagnosis is important for management. Only about 30% of children with an acute demyelinating attack experience clinical and MRI evidence of relapsing disease leading to a diagnosis of MS. While the diagnosis of MS has been historically confirmed with repeated clinical attacks or evidence of new lesions on MRI involving different areas of the CNS, the diagnosis can now be made at the time of a first clinical demyelinating event using the 2010 revised McDonald criteria if the MRI demonstrates clinically silent lesions in two of four regions typical of MS, and provided that at least one of these lesions demonstrates enhancement with gadolinium (box 1) [6,7]. In children, it is also required that the acute presentation not conform to the diagnosis of ADEM [7]. The application of the revised

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To cite this article: Narula S, Banwell B. Treatment of multiple sclerosis in children and its challenges. Presse Med. (2015), http:// dx.doi.org/10.1016/j.lpm.2014.10.018

S. Narula, B. Banwell

Box 1 Diagnostic criteria for pediatric multiple sclerosis [6] The diagnosis of MS can be fulfilled by any of the following:  two or more episodes of CNS demyelination (not ADEM-like) separated by more than 30 days, involving more than one area of the CNS;  a single clinical, non-ADEM event that is associated with MRI features that are consistent with 2010 revised McDonald criteria for dissemination in space1 and with a follow-up MRI that shows at least one new lesion, demonstrating 2010 revised McDonald criteria for dissemination in time2;  one ADEM attack followed by a non-encephalopathic clinical event, three or more months after symptom onset, with new lesions on brain MRI that demonstrate dissemination in space1;  a single acute clinical event that does not meet criteria for ADEM with associated MRI features that meet 2010 Revised McDonald criteria for both dissemination in space1 and dissemination in time2. 1 2010 Revised McDonald MRI criteria for dissemination in space [7]:  the presence of at least one T2 lesion in at least 2 of the following 4 areas of the CNS: periventricular, juxtacortical, infratentorial, or spinal cord. 2 2010 Revised McDonald MRI criteria for dissemination in time [7]:  demonstrated by the appearance of a new T2 or gadoliniumenhancing lesion on a follow-up MRI compared with a baseline scan;  the simultaneous presence of asymptomatic gadoliniumenhancing and non-enhancing lesions at any time. MS: multiple sclerosis; ADEM: acute disseminated encephalomyelitis; CNS: central nervous system.

lesions early in the disease with more infratentorial lesions as compared to patients with adult-onset MS [3,11–13]. Despite having more attacks, pediatric patients tend to have complete and prompt recovery from their relapses and have a slow accrual of physical disability [3,14]. Secondary progressive MS rarely occurs during childhood but has been reported to develop about 20 years after an initial demyelinating event in about half of pediatric-onset patients [3]. When compared to adults, although the time to disability is longer, the age at which secondary progression occurs is generally 10 years younger. Though pediatric patients do not have significant physical disability, cognitive impairment is common early in the disease course (up to 35% of patients) and more than half of children continue to accrue cognitive deficits within the first five years after disease onset [15–18]. Fatigue and depression are also more common in pediatric MS patients as compared to healthy children [19]. Along with the increased recognition and diagnosis of pediatric MS, there has been a significant increase the number of treatment options available. Though none of the current MS therapeutics have been approved by the Food and Drug Administration (FDA) for use in children, and many have been used off-label, the FDA is now mandating that all new drug applications include a plan for pediatric clinical trials. As a result, randomized clinical trials are now underway for a few of the emerging therapies. In the remainder of this article, we will summarize the treatment options available for children with MS (table I) and the challenges associated with treating this group of patients.

First-line disease modifying therapy

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2010 McDonald criteria has now been studied in pediatric MS and demonstrates a positive predictive value of 76% and a negative predictive value of 100% in children older than 11 years [8,9]. Due to the lower positive predictive value in younger children, application of the 2010 criteria at baseline should be applied with caution in this age group [8]. Serial clinical and MRI evaluations are encouraged to confirm relapsing chronic disease. Given that relapse rate is higher in pediatriconset MS patients as compared to patients with adult-onset relapsing remitting MS, the time from first attack to confirmation of MS based on evidence of new disease over time is typically less than 12 months. Pediatric MS manifests with a relapsing remitting disease course. Alternate diagnoses should be considered for all patients with progressive symptoms from onset [10]. As mentioned above, pediatric-onset MS patients have high relapse rates, with more than 75% of children having a second clinical attack within one year. They also have higher cerebrospinal fluid (CSF) white blood cell counts at diagnosis and a higher volume of brain

First-line disease modifying therapies (interferon beta and glatiramer acetate) were initially approved for use in adults 15–20 years ago and have since been safely used in children. Adult studies with these medications have shown a 29–34% reduction in relapse rate and decrease in the development of new MRI lesions as compared with placebo [20–23]. As there have been no randomized controlled trials of these agents in the pediatric population, data on the efficacy, tolerability, and safety of these medications has been primarily garnered from retrospective analyses.

Glatiramer acetate Glatiramer acetate is a heterogenous mixture of synthetic polypeptides consisting of four amino acids (L-alanine, L-glutamic acid, L-lysine, L-tyrosine) found in myelin basic protein. Though its mechanism of action is not fully understood, glatiramer acetate is thought to act as immunomodulator by both shifting the balance of regulatory and effector T-cells and by altering the function of antigen-presenting cells [24,25]. It is an injectable therapy and is typically initiated at the full adult dose in children.

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To cite this article: Narula S, Banwell B. Treatment of multiple sclerosis in children and its challenges. Presse Med. (2015), http:// dx.doi.org/10.1016/j.lpm.2014.10.018 Treatment of multiple sclerosis in children and its challenges

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TABLE I Treatment options for pediatric patients with multiple sclerosis: platform and emerging therapies Medication name

Dose/frequency

Adverse effects

Recommended monitoring

Glatiramer acetate

20 mg daily or 40 mg three times per week via subcutaneous injection

Injection site reactions, immediate post-injection systemic flushing reaction

None

Interferon beta 1a

30 mg weekly via intramuscular injection1 or 44 mg three times per week via subcutaneous injection1

Flu-like symptoms, transaminase elevation, bone marrow suppression, injection site reactions

Monthly CBCs and LFTs for the first 6 months, then every 6 months for the duration of therapy, yearly thyroid studies

Interferon beta 1b

0.25 mg every other day via subcutaneous injection1

Flu-like symptoms, transaminase elevation, bone marrow suppression, injection site reactions

Monthly CBCs and LFTs for the first 6 months, then every 6 months for the duration of therapy, yearly thyroid studies

300 mg every 4 weeks via intravenous infusion

PML, hypersensitivity reaction, transaminase elevation

JC virus antibody testing prior to treatment initiation and then every 3 months while on therapy MRIs should be done frequently when PML risk is high (positive JC virus antibody and duration of treatment > 2 years). LFTs and CBCs should be checked periodically

Induction and maintenance infusion protocols are available; dose is titrated based on lymphocyte count

Nausea, vomiting, alopecia, osteoporosis, bladder cancer, sterility, risk of secondary malignancies

CBC at baseline with repeat testing done 10 days after each infusion, urinalysis should be done before starting infusion and checked with each void during infusion

Teriflunomide2

7 mg or 14 mg daily by mouth3 Pediatric-specific dosing will be available upon completion of its clinical trial

Infections, headaches, transaminase elevation, alopecia, teratogenicity (pregnancy category X)

Prior to first dose: pregnancy test, tuberculin skin test, blood pressure check, CBC, LFTs3 After starting treatment: monthly LFTs for the first 6 months, periodic blood pressure monitoring3 Pediatric-specific screening will be made available upon completion of its clinical trial

Fingolimod2

0.5 mg daily by mouth3 Pediatric-specific dosing will be available upon completion of its clinical trial

Risk of bradycardia with first dose: requires cardiac monitoring by a medical professional for 6 hours. If medication is stopped for 2 weeks or more, cardiac monitoring is again required with the first re-dose Viral infections (especially herpes infections), macular edema, transaminase elevation

Prior to first dose: lymphocyte panel, ophthalmologic evaluation, LFTs, EKG, VZV antibody status3 After starting: ophthalmologic evaluation every 3–6 months, periodic CBCs, LFTs, and lymphocyte panel3 Pediatric-specific screening will be made available upon completion of its clinical trial

Natalizumab

Cyclophosphamide

CBC: complete blood count; EKG: electrocardiogram; LFTs: liver function tests; PML: progressive multifocal leukoencephalopathy; VZV: varicella-zoster virus. 1 Dose should be titrated over 4–6 weeks. 2 Therapy currently under investigation in a pediatric clinical trial. 3 Based on adult studies.

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Interferon beta As with glatiramer acetate, there are likely many mechanisms through which interferon beta exerts its immunomodulatory effect in patients with MS. For instance, it has been suggested

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Retrospective studies evaluating glatiramer acetate in children have shown it to be well tolerated with no significant adverse effects [26–28]. An immediate post-injection systemic flushing reaction with glatiramer acetate can occur, though this is rare.

To cite this article: Narula S, Banwell B. Treatment of multiple sclerosis in children and its challenges. Presse Med. (2015), http:// dx.doi.org/10.1016/j.lpm.2014.10.018

S. Narula, B. Banwell

that interferon beta may inhibit T-cell activation and proliferation, induce regulatory T-cells, modulate cytokines, and reduce lymphocyte migration as part of its therapeutic effect [29]. Injectable versions of interferon beta 1a and -1b, have been used and retrospectively evaluated in the pediatric MS population. While interferon beta has been reported to be generally well tolerated, side effects including a transient elevation of liver transaminases, and rarely bone marrow suppression, characterized by either leukopenia, anemia, thrombocytopenia, can occur. The most commonly reported side effects with interferon beta are flu-like symptoms (myalgias, chills) though these are less commonly noted when the dose is slowly uptitrated over 4 to 6 weeks [30–32]. As liver function test (LFT) abnormalities most commonly occur in the first 6 months of therapy, monthly monitoring of transaminases during this initial time period is recommended as is subsequent re-evaluation every 6 months thereafter. Should transaminases increase while on therapy, a reduction of dose may result in normalization of laboratory abnormalities and the interferon may be again titrated to full dose after some period of time, or a switch in disease modifying therapy could also be considered [33,34].

Second-line disease modifying therapy In a study of 258 pediatric patients with MS who were followed for at least 6 months (mean 3.9 years), about half switched therapy because of either intolerable side effects (16%) or treatment failure (28%) [35]. As there are a significant number of patients with aggressive disease who are inadequately controlled with first-line disease modifying therapy, use of newer, more effective medications has become more common in recent years. However, with the long-term safety of these therapies not yet fully understood, the relative risks and benefits should always be considered and discussed prior to initiation.

Natalizumab

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Natalizumab is a humanized monoclonal antibody that targets the a4 subunit of a4b1 and 4b7 integrins, which are molecules that are involved in the transmigration of immune cells into the CNS. By blocking the interaction of these molecules with their receptors on vascular endothelium, natalizumab effectively prevents these cells from getting across the blood brain barrier [36]. Natalizumab is one of the most effective medications for relapsing MS and has been shown to decrease relapse rate 68% as compared to placebo in adults [37]. There have been a number of retrospective studies that have evaluated the efficacy and tolerability of natalizumab in children [38–43]. The largest study to date is one of 55 pediatric MS patients who were placed on natalizumab in the setting of breakthrough disease. They reported that only three patients

had a relapse during the observation period and that the mean expanded disability status scores (EDSS) decreased from 2.7 to 1.9 [43]. These studies also found natalizumab to be well tolerated by children. Progressive multifocal leukoencephalopathy (PML) is the most serious associated side effect of natalizumab and the main reason why its use is limited in the pediatric MS population. PML is a potentially fatal brain infection caused by reactivation of an ubiquitous polyomavirus, the JC virus. PML is thought to result from infection and destruction of oligodendrocytes, leading to multifocal areas of demyelination [44]. PML occurs in patients exposed to natalizumab due to decreased immune surveillance that results from decreased lymphocyte trafficking into the brain [45]. The risk of PML in natalizumab-treated MS patients increases with prior exposure to the JC virus, increased time on natalizumab treatment, and previous exposure to immunosuppressive drugs (ex: cyclophosphamide, mitoxantrone, azathioprine). Though it was previously thought that infection with JC virus occurred in adolescence or adulthood, a recent study of the prevalence of JC virus antibodies in a cohort of German pediatric MS patients found about half of the cohort to be seropositive. Additionally, on follow-up testing, a 4.3% seroconversion rate was found in this group [46]. Therefore, regular evaluation of a patient's JC virus antibody status while on natalizumab is essential to adequately assess PML risk.

Cyclophosphamide Cyclophosphamide is an alkylating agent that has also been used a second-line therapy in pediatric MS. In one retrospective study of 17 active MS patients (mean EDSS of 3.7) treated with cyclophosphamide, relapse rate decreased and disability scores stabilized in the majority of patients after one year of treatment [47]. Side effects did occur and included vomiting, transient alopecia, osteoporosis, and amenorrhea. One patient developed bladder cancer and another developed sterility (though this was not formally assessed in most patients) [47]. Additionally, though not reported in this cohort, there is a risk of secondary malignancy when cyclophosphamide is used. As a result of these potential side effects, use of cyclophosphamide is limited in pediatric MS patients.

Emerging agents Several new oral therapies have been approved for use in adults with MS in the past few years. To date, fingolimod, teriflunomide, and dimethyl fumarate are the only oral compounds that have been approved for use in adults by the FDA. Pediatric clinical trials are now underway for fingolimod and teriflunomide and will inform on both efficacy and safety of these medications and the difficulties of performing clinical trials in this population. As there are many other emerging therapies that are poised for approval for adults, including chemotherapeutic agents and monoclonal antibodies, it will be an

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To cite this article: Narula S, Banwell B. Treatment of multiple sclerosis in children and its challenges. Presse Med. (2015), http:// dx.doi.org/10.1016/j.lpm.2014.10.018 Treatment of multiple sclerosis in children and its challenges

imperative to understand the challenges with conducting clinical trials in these patients and to reinforce collaboration among centers to encourage recruitment and retention of their subjects.

Treatment challenges in pediatric MS While all of the available MS therapeutics do work to reduce relapse rate and lesion accrual, they are all only partially effective and do not completely eliminate disease activity. Therefore, as breakthrough disease is likely to occur in a proportion of patients, it is important to have criteria that adequately identify patients with an inadequate response to therapy. As pediatric MS patients do typically have a higher relapse rate and a greater MRI lesion burden as compared to adults, it is important for providers to use standardized pediatric-specific criteria when trying to identify patients with an inadequate response to therapy. In 2012, the International Pediatric Multiple Sclerosis Study Group (IPMSSG), a group of international collaborating physicians and researchers treating children with MS, put forth guidelines for assessment of treatment efficacy by providers. The guidelines require that patients be treated for at least 6 months on full dose therapy and are fully compliant. Inadequate treatment is defined by either an increase or no reduction in relapse rate, new T2 or contrasting lesions on MRI as compared to pre-treatment, or two or more confirmed clinical exacerbations within a 12-month period or less [48]. Aside from these criteria, factors such as the presence of poor

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recovery from relapses and evidence of disease progression in the absence of relapses may also warrant a change in therapy. Change in physical impairment, as measured by the EDSS score, may not be the most appropriate marker to assess treatment response as children do not typically accrue physical disability early in the disease, and are more likely to endorse cognitive symptoms or fatigue, which are not adequately measured by this scale. Many adolescents with MS have difficulty adhering to disease modifying therapy [49]. Tolerability for injectable treatments is a challenge for all MS patients. Thus, the attraction to new oral therapies is clearly evident. However, adherence is important for oral therapies as well, as emphasized by the cardiac risks associated with the first dose (or re-dose after a period off treatment) for the oral agent, fingolimod. Though pediatric MS remains a rare disease and providers and researchers continue to face challenges, worldwide collaborations are ongoing to develop updated treatment algorithms and to ensure safe application of emerging therapeutics. It is encouraging the first pediatric clinical trials in MS are now underway, as are plans for prospective registries that will help to assess longterm safety risks of these medications. Disclosure of interest: Dr. Narula declares that he has no conflicts of interest concerning this article. Dr. Banwell serves as a consultant for Novartis, Biogen-IDEC, and Sanofi Aventis. None of this effort has any relationship with the present manuscript.

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